Oral Contraceptives to Prevent Pregnancy and Diminish Premenstrual Symptomatology

ABSTRACT

This invention relates to a method of preventing pregnancy and treating PMS including PMDD. More particularly, the invention relates to a method, which involves administering one of several combination oral contraceptive regimens in combination with an antidepressant and a kit containing the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.10/309,313, filed Dec. 4, 2002, which claims the benefit of U.S.Provisional Application No. 60/335,807, filed Dec. 5, 2001. Thedisclosures of both of these applications are hereby incorporated hereinby reference in their entireties.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to oral contraceptives that prevent pregnancy anddiminish or eliminate premenstrual symptomatology, including PMS andPMDD, and to a method of preventing pregnancy and diminishing oreliminating premenstrual symptomatology, including PMS and PMDD.

2. Background Art

The human menstrual cycle involves a repetitive sequence of hormonalchanges that result in episodic uterine bleeding. Normally, eachmenstrual cycle has a mean interval of 21 to 35 days, conventionallybeginning with the first day of menstrual flow and ending on the daybefore the next onset of bleeding. Duration of the menstrual flow isusually 2 to 6 days with loss of 20 to 60 ml of blood.

The menstrual cycle is divided into follicular and luteal phases, eachcorresponding to changes occurring in the ovary. These phases may alsobe described as proliferative or secretory, corresponding to changesobserved in the uterine endometrium. Variations in the length of thecycle are usually due to alterations in the follicular phase, becausethe luteal phase length remains relatively constant at 12 to 16 days.

During the follicular phase, several primary follicles are recruited forfurther growth and development. Granulosa cells in primary folliclesposses follicle stimulating hormone (FSH) and estradiol receptors. UponFSH stimulation, granulosa cells produce aromatase. This enzyme convertsthe androgens androstenedione and testosterone, made in response toluteinizing hormone (LH) by thecal cells, to estrone and estradiol,respectively. Granulosa cells respond to estradiol by undergoing mitosisto increase the number of granulosa cells and estradiol production. Byday 7 of the cycle, one enlarging primary follicle is selected byunknown processes to be the follicle that will release the oocyte atovulation.

The midcycle rise in plasma estradiol stimulates the large midcycle LHsurge. This midcycle LH surge triggers resumption of meiosis within theoocyte and luteinization of the granulosa cells within the preovulatoryfollicle. Immediately before ovulation, the outer follicular wall beginsto dissolve and an oocyte is released approximately 24 to 36 hours fromthe onset of the LH surge.

After ovulation, granulosa cells and the surrounding theca cellsenlarge, accumulate lipid, and become transformed into lutein cells.This begins the luteal phase of the menstrual cycle. These cells form anew vascularized structure called the corpus luteum, which secretesestradiol and progesterone. LH maintains the corpus luteum during theluteal phase and, acting via the adenyl cyclase system, stimulatesprogesterone production. If pregnancy does not occur, lutein cellsdegenerate, and diminished hormone secretion precedes menstruation.Menstruation is immediately followed by the onset of another menstrualcycle.

Because endometrial proliferation serves to prepare the uterus for animpending pregnancy, manipulation of hormones and of the uterineenvironment can provide contraception. For example, estrogens are knownto decrease FSH secretion by feedback inhibition. Under certaincircumstances, estrogens can also inhibit LH secretion, once again bynegative feedback. Under normal circumstances, the spike of circulatingestrogen found just prior to ovulation induces the surge of gonadotropichormones that occurs just prior to and results in ovulation. High dosesof estrogen immediately post-coitally also can prevent conceptionprobably due to interference with implantation.

Progestins can also provide contraception. Endogenous progesterone afterestrogen is responsible for the progestational changes of theendometrium and the cyclic changes of cells and tissue in the cervix andthe vagina. Administration of progestin makes the cervical mucus thick,tenacious and cellular which is believed to impede spermatozoaltransport. Administration of progestin also inhibits LH secretion andblocks ovulation in humans.

The most prevalent form of oral contraception is a pill that combinesboth an estrogen and a progestin, a so-called combined oralcontraceptive preparation.

Alternatively, there are contraceptive preparations that compriseprogestin only. However, the progestin-only preparations have a morevaried spectrum of side effects than do the combined preparations,especially more breakthrough bleeding. As a result, the combinedpreparations are the preferred oral contraceptives in use today (Shethet al., Contraception 25:243 (1982)).

In establishing an estrogen-progestin regimen for oral contraceptives,two principal issues must be confronted. First, efficacy must bemaintained and second, there must be avoidance of further erosion in thecontrol of endometrial bleeding. In general, even the lowest dose oralcontraceptive products commercially available have demonstrated efficacybut the overall instances of bleeding control problems have increased asthe doses were reduced, as manifested both in breakthrough bleeding(untimely flow or spotting) or withdrawal amenorrhea during the “pillfree” week (expected menses).

During the luteal phase of the menstrual cycle, as many as 75% of womenwith regular menstrual cycles experience some symptoms of premenstrualsyndrome (PMS), a recurring, cyclical disorder involving behavioral,emotional, social and physical symptoms (Steiner et al., Annu. Rev. Med.48:447-455 (1997)). Behavioral, emotional and social symptoms include,but are not limited to, irritability, mood swings, depression, hostilityand social withdrawal. Physical symptoms include, but are not limitedto, bloating, breast tenderness, myalgia, migraines or headaches andfatigue. True PMS only occurs during the luteal phase of the menstrualcycle, with a symptom-free period during the follicular phase. Theetiology of PMS is still unknown.

A subgroup of women with PMS, about 2-9%, exhibit symptoms that areprimarily related to a severe mood disorder. In these women, thediagnosis of Premenstrual Dysphoric Disorder (PMDD), which is defined inthe Fourth edition of the Diagnostic and Statistical Manual of MentalDisorders (DSM-IV) can be applied. According to the DSM-IV, a woman withPMDD must have at least five premenstrual symptoms during the lutealphase, with at least one of the symptoms being an emotional or “core”symptom. The core symptoms must be irritability, anger, mood swings,tension or depression (and interfere with daily activities), and must beconfirmed by a prospective daily rating for at least two cycles. Threeto five percent of women with PMS report to have PMDD.

There is also a subgroup of women who experience severe PMS, whichaccounts for about 20% of the PMS population. These women experiencesevere emotional symptoms that do not fall under the strict criteria ofPMDD as defined in DSM-IV but require medical attention.

Symptoms of PMDD may begin at any age after menarche, but the averageage at onset appears to be around 26 years and several researchers foundthat symptoms, such as estrogen withdrawal symptoms, associated with thepremenstrual phase gradually become worse, and perhaps more protracted,over time. It has been suggested that worsening could occur because ofthe recurring increases and decreases in ovarian hormones. This issupported by data from other cultures: when menstruation is infrequent,premenstrual symptoms are rare. It is also supported by data associatinglow parity with the risk of PMDD. Low parity yields a greater number ofhormonal cycles, and, thus, a woman has more exposure to and withdrawalfrom massive amounts of progesterone. Further, several studies findlower rates of premenstrual symptoms among users of oral contraceptives,again suggesting that briefer exposure to peaks and troughs ofendogenous progesterone is protective against PMDD (Yonkers, K., J.Clin. Psychiatry 58(Suppl. 14): 4-13 (1997)).

Suppression of ovulation has been an important rationale for the use ofhormonal treatments for PMS. One method of inhibiting ovulation is byusing oral contraceptives (OCs). Combination oral contraceptives inhibitovulation by suppressing gonadotropins, follicle stimulating hormone(FSH) and luteinizing hormone (LH). To date, only two controlled studiesof the oral contraceptive treatment of PMS have been published. Theresults indicate that combination oral contraceptives effectively reducephysical symptoms (especially breast pain and bloating), but theresponse on the relief of psychological symptoms has been less clear.

Therapeutic interventions for women who meet the criteria for PMDDinclude selective serotonin reuptake inhibitors (SSRI), tricyclicantidepressants and anxiolytics, as well as the antidepressantalprazolam (XANAX®). These interventions have demonstrated efficacy withminimal side effects. Recent investigations of SSRI have alsodemonstrated success at low doses.

Antidepressants that are active at serotonin receptors includeclomipramine (ANAFRANIL®), fluoxetine (PROZAC®), paroxetine (PAXIL®),sertraline (ZOLOFT®), nefazodone (SERZONE®), fenfluramine (PONDIMIN®)and venlafaxine (EFFEXOR®).

The only approved product today for the treatment of PMDD is the SSRIfluoxetine hydrochloride (SARAFEM®). The effectiveness of fluoxetine forthe treatment of PMDD was established in four randomized,placebo-controlled trials. Fluoxetine at a daily dose of either 20 mg or60 mg proved to be superior to placebo in reducing symptoms (Steiner etal., New Engl. J. Med. 332:1529-34 (1995)). However, the combination oforal contraceptive and fluoxetine was not examined, as women who weretaking oral contraceptives were excluded from the trial.

It is the object of the present invention to provide estrogen-progestincombinations and/or regimens for oral contraceptive use, includingestrogen-progestin combinations and/or regimens that contain anantidepressant, to concurrently diminish or eliminate premenstrualsymptoms (PMS) including PMDD. Two regimens are proposed, the so-called28-day regimen and the 91-day regimen. The 28-day regimen will allowwomen the option of maintaining the customary 13 menstrual cycles peryear while diminishing or alleviating premenstrual symptoms (PMS)including PMDD. The 91-day regimen will allow women the option ofmaintaining only 4 menstrual cycles per year while diminishing oralleviating premenstrual symptoms (PMS) including PMDD. Thus, the 91-dayregimen enhances compliance by involving fewer stop/start transitionsper year and also results in less blood loss, and hypothetically, willdiminish premenstrual symptoms, including PMDD. Having fewer menstrualintervals can also enhance lifestyles and convenience. This and otherobjects of the invention will become apparent to those skilled in theart from the following detailed description.

BRIEF SUMMARY OF THE INVENTION

This invention relates to female oral contraceptives that will preventpregnancy and treat PMS including PMDD. This invention further relatesto a method of preventing pregnancy and treating PMS including PMDD, byavoiding complete withdrawal of estrogen at the end of the treatmentperiod, or between treatment periods, by administering oralcontraceptives. Premenstrual symptoms are rare when menstruation isinfrequent. Further, users of oral contraceptives have lower rates ofpremenstrual symptoms, again suggesting that briefer exposure to peaksand troughs of endogenous progesterone is protective against PMDD. Moreparticularly, the invention relates to a method of preventing pregnancy,which involves administering one of two combination oral contraceptiveregimens. Additionally, the invention relates to a method of preventingpregnancy, which involves administering one of two combination oralcontraceptive regimens that contain an antidepressant.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to oral contraceptives that will prevent pregnancyand diminish or eliminate PMS including PMDD. Methods of using theseoral contraceptives to prevent pregnancy and diminish or eliminate PMSincluding PMDD are also provided. More particularly, the methods involveadministering one of several combination oral contraceptive regimens.Importantly, these regimens do not contain pill-free or placebointervals.

One embodiment of the invention is the so-called twenty-eight dayregimen that allows women the option of maintaining 13 menstrual cyclesper year. In accordance with the present invention, a women in need ofcontraception and treatment of PMS including PMDD, is administered acombined dosage form of estrogen and progestin, preferably monophasicly,for 21 to 26 consecutive days, preferably about 22-25 days, followed byadministration of low-dose estrogen for 2 to 10 days, preferably about3-7 days, more preferably about 2-7 days, in which the daily amounts ofestrogen and progestin are equivalent to about 5-50 μg of ethinylestradiol and about 0.025 to 10 mg, preferably about 0.05 to 1.5 mg, oflevonorgestrel, respectively.

In a preferred embodiment, women will be administered an oralcontraceptive on days 1 through 21 of the menstrual cycle containing 150μg levonorgestrel and 30 μg ethinyl estradiol, followed by a dosage formon days 22-28 of the cycle, which contains 30 μg ethinyl estradiol. Atypical administration schedule is illustrated in Table 1. Thus, in a28-day regimen schedule, there are about 13 treatment and menstrualcycles per year.

TABLE 1 Administration schedule for a 28-day regimen Days HormoneAntidepressant  1-21 150 μg levonorgestrel and none  30 μg ethinylestradiol 22-28  30 μg ethinyl estradiol none

In another embodiment of the invention, a women in need of contraceptionand treatment of PMS including PMDD, is administered a combined dosageform of estrogen and progestin, preferably monophasicly, for 21 to 26consecutive days, preferably about 22-25 days, followed byadministration of low-dose estrogen for 2 to 10 days, preferably about3-7 days, more preferably about 2-7 days, in combination with theantidepressant fluoxetine hydrochloride, in which the daily amounts ofestrogen and progestin are equivalent to about 5-50 μg of ethinylestradiol and about 0.025 to 10 mg, preferably about 0.05 to 1.5 mg, oflevonorgestrel, respectively, and the fluoxetine hydrochloride is in anamount of about 5-120 mg. Oral contraceptives with initial doses offluoxetine at either 5 mg or 10 mg/day can be started to avoid anyactivating side effects that may lead to noncompliance. The dose canthen be increased as needed. Fluoxetine can also be given intermittentlyduring the late luteal phase, which is typically 1-2 weeks beforemenses. In addition, a one-time or once-weekly dose of about 90 mg offluoxetine can be administered.

In a preferred embodiment, women will be administered an oralcontraceptive on days 1 through 21 of the menstrual cycle containing 150μg levonorgestrel and 30 μg ethinyl estradiol, followed by a dosage formon days 22-28 of the cycle, which contains 20 mg fluoxetinehydrochloride and 30 μg ethinyl estradiol. A typical administrationschedule is illustrated in Table 2. Thus, in a 28-day regimen schedule,there are about 13 treatment and menstrual cycles per year.

TABLE 2 Administration schedule for a 28-day regimen with anantidepressant Days Hormone Antidepressant  1-21 150 μg levonorgestreland none  30 μg ethinyl estradiol 22-28  30 μg ethinyl estradiol 20 mgfluoxetine hydrochloride daily OR a one-time dose of 90 mg fluoxetinehydrochloride OR a once-weekly dose of 90 mg fluoxetine hydrochloride

An additional embodiment of the invention is a long-term regimen thatallows women the option of limiting their menstrual periods to aboutfour times per year. In accordance with the present invention, a womenin need of contraception and treatment of PMS including PMDD, isadministered a combined dosage form of estrogen and progestin,preferably monophasicly, for 60 to 110 consecutive days, preferablyabout 81 to 89 days, followed by administration of estrogen for 2 to 10days, preferably about 5 to 8 days, in which the daily amounts ofestrogen and progestin are equivalent to about 5-50 μg of ethinylestradiol and about 0.025 to 10 mg, preferably about 0.05 to 1.5 mg, oflevonorgestrel, respectively.

In a preferred embodiment, the 91-day regimen, women will beadministered an oral contraceptive on days 1 through 84 of the menstrualcycle containing 150 μg levonorgestrel and 30 μg ethinyl estradiol,followed by a dosage form on days 85-91 of the cycle, which contains 30μg ethinyl estradiol. A typical administration schedule is illustratedin Table 3. Thus, in a 91-day regimen, there are only four treatment andmenstrual cycles per year.

TABLE 3 Administration schedule for a 91-day regimen Days HormoneAntidepressant  1-84 150 μg levonorgestrel and none  30 μg ethinylestradiol 85-91  30 μg ethinyl estradiol none

In an additional embodiment of the invention, a women in need ofcontraception and treatment of PMS including PMDD, is administered acombined dosage form of estrogen and progestin, preferably monophasicly,for 60 to 110 consecutive days, preferably about 81 to 89 days, followedby administration of low-dose estrogen and fluoxetine hydrochloride for2 to 10 days, preferably about 5 to 8 days, in which the daily amountsof estrogen and progestin are equivalent to about 5-50 μg of ethinylestradiol and about 0.025 to 10 mg, preferably about 0.05 to 1.5 mg, oflevonorgestrel, respectively, and the fluoxetine hydrochloride is in anamount of about 5-120 mg. Oral contraceptives with initial doses offluoxetine at either 5 mg or 10 mg/day can be started to avoid anyactivating side effects that may lead to noncompliance. The dose canthen be increased as needed. Fluoxetine can also be given intermittentlyduring the late luteal phase, which is typically 1-2 weeks beforemenses. In addition, a one-time or once-weekly dose of about 90 mg offluoxetine can be administered.

In a preferred embodiment, women will be administered an oralcontraceptive on days 1 through 84 of the menstrual cycle containing 150μg levonorgestrel and 30 μg ethinyl estradiol, followed by a dosage formon days 85-91 of the cycle, which contains 30 μg ethinyl estradiol and20 mg fluoxetine hydrochloride. A typical administration schedule isillustrated in Table 4. Thus, in a 91-day regimen, there are only fourtreatment and menstrual cycles per year.

TABLE 4 Administration schedule for a 91-day regimen with anantidepressant Days Hormone Antidepressant  1-84 150 μg levonorgestreland none  30 μg ethinyl estradiol 85-91  30 μg ethinyl estradiol 20 mgfluoxetine hydrochloride daily OR a one-time dose of 90 mg fluoxetinehydrochloride OR a once-weekly dose of 90 mg fluoxetine hydrochloride

The estrogens which may be employed as a component in the regimens ofthis invention may be any of those conventionally available. Typically,the estrogen may be selected from the group comprising synthetic andnatural estrogens, including steroidal and nonsteroidal estrogens. Thesynthetic estrogens may be selected from, for example, ethinylestradiol, ethynodiol diacetate, mestranol and quinestranol.Particularly of interest are 17α-ethinyl estradiol and esters and ethersthereof. The preferred estrogen is 17α-ethinyl estradiol. The naturalestrogens may include, for example, conjugated equine estrogens,esterified estrogens, 17β-estradiol, estradiol valerate, estrone,piperazine estrone sulphate, estriol, estriol succinate and polyestrolphosphate.

The progestin component may be any progestationally active compound.Thus, the progestin may be selected from progesterone and itsderivatives such as, for example, 17-hydroxy progesterone esters,19-nor-17-hydroxy progesterone esters, 17α-ethinyltestosterone andderivatives thereof, 17α-ethinyl-19-nor-testosterone and derivativesthereof, norethindrone, norethindrone acetate, ethynodiol diacetate,dydrogesterone, medroxy-progesterone acetate, norethynodrel,allylestrenol, lynoestrenol, fuingestanol acetate, medrogestone,norgestrienone, dimethiderome, ethisterone, cyproterone acetate,levonorgestrel, dl-norgestrel,d-17α-acetoxy-13β-ethyl-17α-ethinyl-gon-4-en-3-one oxime, cyproteroneacetate, gestodene, desogestrel and norgestimate. The preferredprogestin is levonorgestrel.

The weight ratio of the active ingredients, e.g., ethinyl estradiol andlevonorgestrel, is at least 1:45 and preferably at least 1:50. Thepreferable amount of ethinyl estradiol is about 10-50 μg and thepreferable amount of levonorgestrel is about 0.15-1.5 mg. Otherestrogens vary in potency from ethinyl estradiol. For example, 30 μg ofethinyl estradiol is roughly equivalent to 60 μg of mestranol or 2 g of17β-estradiol. Likewise, other progestins vary in potency fromlevonorgestrel. Thus, 1 mg of levonorgestrel is roughly equivalent toabout 3.5 mg of norethindrone acetate, or 1 mg of desogestrel and3-ketodesogestrel or about 0.7 mg of gestodene. The values given aboveare for ethinyl estradiol and levonorgestrel and if a different estrogenor progestin is employed, an adjustment in the amount based on therelative potency should be made. The correlations in potency between thevarious estrogens and progestins are known. See for example EuropeanPatent Application No. 0 253 607, which is hereby incorporated in itsentirety by reference hereto.

The preferred antidepressant is fluoxetine hydrochloride although otherantidepressants can be employed. For example, the antidepressantsalprazolam (XANAX®), clomipramine (ANAFRANIL®), paroxetine (PAXIL®),sertraline (ZOLOFT®), nefazodone (SERZONE®), fenfluramine (PONDIMIN®)and venlafaxine (EFFEXOR®) can also be used. The daily amounts of theseantidepressants can vary, depending on the antidepressant used, from0.75 to 2 mg, 10 to 20 mg or 50 to 100 mg.

Each of the described regimens will prevent pregnancy and additionallydiminish or eliminate debilitating premenstrual symptomatology.

Other useable estrogens include the esters of estradiol, estrone andethinyl estradiol such as the acetate, sulfate, valerate or benzoate,conjugated equine estrogens, agnostic anti-estrogens, and selectiveestrogen receptor modulators. The formulations of the invention may beadministered orally, preferably in tablet form, parenterally,sublingually, transdermally, intravaginally, intranasally or buccally.The method of administration depends on the types of estrogens andprogestins used in the formulation, as well as the amounts per unitdosage. Most estrogens are orally active and that route ofadministration is therefore preferred. Methods for transdermaladministration including the associated methods for manufacturing suchsystems are well known in the art. In this connection, reference may behad to U.S. Pat. Nos. 4,752,478, 4,685,911, 4,438,139 and 4,291,014,which are hereby incorporated in their entirety by reference hereto.

Pharmaceutical formulations or preparations containing the formulationsof the invention and a suitable carrier can be solid dosage forms whichincludes tablets, dragees, capsules, cachets, pellets, pills, powders orgranules; topical dosage forms which include solutions, powders, fluidemulsions, fluid suspensions, semi-solids, ointments, pastes, creams,gels or jellies, foams and controlled release depot entities;transdermals, vaginal rings, buccal formulations; and parenteral dosageforms which includes solutions, suspensions, emulsions or dry powdercomprising an effective amount of estrogen, progestin and antidepressantas taught in this invention.

It is known in the art that active ingredients can be contained in suchformulations in addition to pharmaceutically acceptable diluents,fillers, disintegrants, binders, lubricants, surfactants, hydrophobicvehicles, water soluble vehicles, emulsifiers, buffers, humectants,moisturizers, solubilizers, preservatives and the like. The means andmethods for administration are known in the art and an artisan can referto various pharmacologic references for guidance. For example, “ModernPharmaceutics”, Banker & Rhodes, Marcel Dekker, Inc. (1979); “Goodman &Gilman's The Pharmaceutical Basis of Therapeutics”, 6th Edition,MacMillan Publishing Co., New York (1980), or Remington's PharmaceuticalSciences, Osol, A., ed., Mack Publishing Company, Easton, Pa. (1980) canbe consulted.

Generally speaking, the formulations are prepared according toconventionally known procedures in accordance with the method ofadministration. Thus, the active ingredients are prepared according toknown methods in a pharmaceutically acceptable form for administration.These ingredients, in their required quantities are combined with theappropriate pharmaceutical carriers such as additives, vehicles and/orflavor ameliorating substances. These substances may be referred to asdiluents, binders and lubricants. Gums, starches and sugars are alsocommon terms. Typical of these types of substances or excipients arepharmaceutical grades of mannitol, lactose starch, magnesium stearate,sodium saccharin, talcum, cellulose, glucose, sucrose, magnesiumcarbonate and the like. The active ingredient(s) may comprise from about0.01% by weight to about 99.99% by weight of the total formulation andthe remainder comprises the pharmaceutically acceptable carrier. Thepercentage of active ingredient(s) may vary according to the deliverysystem or method of administration and is chosen in accordance withconventional methods known in the art.

In the oral form of the formulation, the contraceptive preparations arepreferably produced in the form of a kit or package, with the dailydosages arranged for proper sequential administration. Thus, in anotheraspect, the present invention also provides a pharmaceutical packagewhich contains combination-type contraceptives in multiple dosage unitsin a synchronized, fixed sequence, wherein the sequence or arrangementof the dosage units corresponds to the stages of daily administration.

For example, the pharmaceutical formulations may be provided in kit formcontaining for the 28-day regimen at least about 18, and preferably atleast about 21 tablets, and up to 26 tablets, intended for ingestion onsuccessive days. Preferably administration is daily for at least 21 daysusing tablets containing both the estrogen and the progestin and thenfor at least 7 days using tablets containing only estrogen. In anotherpreferred embodiment, administration is daily for at least 21 days usingtablets containing both the estrogen and the progestin and then for atleast 7 days using tablets containing both estrogen and anantidepressant, e.g., fluoxetine hydrochloride. For the long-termregimen, the pharmaceutical formulation may be provided in kit formcontaining at least about 60, and preferably at least about 81 to 89tablets, and up to 110 tablets, intended for ingestion on successivedays. Preferably administration is daily for at least 84 days usingtablets containing both the estrogen and the progestin and then for atleast 7 days using tablets with only estrogen. In another preferredembodiment, administration is daily for at least 84 days using tabletscontaining both the estrogen and the progestin and then for at least 7days using tablets with both estrogen and an antidepressant, e.g.,fluoxetine hydrochloride.

Efficacy of the 28-day and 91-day regimens on premenstrualsymptomatology are measured by psychometric scales that includeself-administered Visual Analogue Scales (VAS) and a prospective dailysymptoms chart or diary to evaluate psychological and somatic symptoms.Total score of the psychological and somatic symptoms is computed. TheVAS measures tension, irritability, dysphoria, sleeping and eatingpatterns, headache, bloating, pain and breast tenderness and weight gainsymptoms.

In order to further illustrate the present invention, specific examplesare set forth below. It will be appreciated, however, that theseexamples are illustrative only and are not intended to limit the scopeof the invention.

EXAMPLES Example 1 Multicenter Randomized Phase III Clinical Trial toEvaluate Two Continuous Oral Contraceptive Regimens in Women Diagnosedwith Premenstrual Syndrome (PMS) and Premenstrual Dysphoric Disorder(PMDD)

Clinical Design and Summary

In a multicenter, randomized, clinical trial the efficacy and safety ofthree combination oral contraceptives regimens in the prevention ofpregnancy in sexually active women, ages 18 through 40 years, will beevaluated. Patients will be randomized in a 1:1:1 fashion to one of thefollowing regimens:

-   -   Levonorgestrel 150 μg/ethinyl estradiol (EE) 30 μg administered        once daily for 84 days as a combination oral tablet followed by        ethinyl estradiol 30 μg administered once daily for 7 days        (DP3-84/30);    -   Levonorgestrel 150 μg/ethinyl estradiol 30 μg administered once        daily for 84 days as a combination oral tablet followed by        ethinyl estradiol 10 μg administered once daily for 7 days        (DP3-84/10); or    -   Levonorgestrel 150 μg/ethinyl estradiol 30 μg administered once        daily for 25 days as a combination oral tablet followed by        ethinyl estradiol 30 μg administered once daily for 3 days        (DP3-25/30). Patients randomized to either DP3-84/30 or        DP3-84/10 will receive 4 cycles of study drug. Patients        randomized to DP3-25/30 will receive 13 cycles of study drug.        All patients will receive approximately 1 year of therapy.

The study coordinator or designated personnel will register the patient.Patients will be randomly assigned to one of the treatment regimens. Thetreatment group assignment will not be revealed to the patient prior tosigning of the informed consent.

All patients, regardless of randomization, will initiate study OCtherapy on the first Sunday following the beginning of their menstrualperiod (“Sunday starters”) and will remain as Sunday starters throughoutthe study. Each of the dose packs will be dispensed with an abbreviatedpatient information sheet and a more detailed patient package insert(PPI).

All patients will complete and download information entered into anelectronic diary. Assessments will include study drug compliance, use ofadditional forms of contraception, bleeding patterns, weight, assessmentof the incidence and severity of menstrual related symptoms andmedication taken to relieve these symptoms. Information will beself-recorded on the electronic diary via a series of pre-programmedquestions.

Two hundred (200) patients in each treatment arm are targeted tocomplete the study. Pregnancy rate will be calculated using data fromthose patients age 18 to 35. Patients age 36 through 40 will also beenrolled.

Patient Eligibility

Inclusion Criteria

Patients must meet the following criteria to be included in the study:

-   1. Sexually active adult females (age 18 through 40), of child    bearing potential, in a heterosexual relationship, at risk for    pregnancy, who are in good health and who    -   have a history of OC use for an interval of at least three        successive cycles with regular withdrawal bleeding (bleeding        during the pill-free interval or during the first three days of        the subsequent cycle) prior to enrollment (Continuous Users)        -   OR    -   have no prior history OC use (Fresh-Starts)        -   OR    -   have no history of OC use in the 6 months prior to enrollment        (Prior Users)-   2. Negative urine pregnancy test.-   3. Signed informed consent.-   4. Agree to use study oral contraceptive therapy as their primary    birth control method (BCM).

Exclusion Criteria:

Patients will be excluded from the study if any of the followingcriteria are met:

-   1. History of hypersensitivity to estrogen or progestin components    of OCs.-   2. History of alcohol or drug abuse which, in the opinion of the    investigator, makes the patient unfit for participation in the    study.-   3. Active smoker age >34 years.-   4. Chronic use of any medication that may interfere with the    efficacy of oral contraceptives.-   5. History of being HIV or Hepatitis C positive.-   6. History of persistent noncompliance with any chronic medication.-   7. History of having received injectable hormone therapy (e.g.,    Depo-Provera<(Pharmacia and Upjohn)) within the 10 months prior to    enrollment or having a progestin-releasing intrauterine device (IUD)    in place within 3 months prior to enrollment or has had a    contraceptive implant removed within one month prior to enrollment    or has received any other form of hormonal contraception within 3    months prior to enrollment.-   8. Routine concomitant use of additional forms of contraception    (IUD, diaphragm, contraceptive sponge) with the exception of    condoms.-   9. Patients who have had recent surgical or medical abortion,    miscarriage, or vaginal or cesarean delivery must have had at least    two normal menstrual cycles prior to enrollment.-   10. History of abnormal bleeding (breakthrough or withdrawal    bleeding that lasts≧10 consecutive days or excessive spotting that    lasts≧10 consecutive days) while on conventional oral    contraceptives.-   11. History of thromboembolic disorder, vascular disease, cerebral    vascular or coronary artery disease.-   12. Uncontrolled or untreated hypertension (systolic BP≧140 mmHg and    diastolic BP≧90 mmHg on more than two occasions).-   13. Known or suspected carcinoma of the breast, endometrial    carcinoma or known or suspected estrogen dependent neoplasia.-   14. Undiagnosed abnormal genital bleeding.-   15. History of hepatic adenomas or carcinomas.-   16. History of cholestatic jaundice of pregnancy or jaundice with    prior OC use.-   17. Known or suspected pregnancy or currently breastfeeding.-   18. Hyperlipidemia requiring active treatment with    antihyperlipidemic agents.-   19. History of diabetes mellitus, glucose intolerance or gestational    diabetes.-   20. History of abnormal laboratory value at screening-   21. Any clinically significant abnormal finding or condition on    history, screening, physical exam, pelvic exam or any laboratory    finding which contraindicates the use of oral contraceptives.-   22. Has participated in any clinical investigation within the 30    days prior to enrollment.-   23. Has donated or had a loss of more than 500 cc of blood within    the 30 days prior to enrollment.

Treatment Regimen

Description of Study Medication

DP3-84/30

All tablets in the DP3-84/30 regimen; 84 tablets each containing 150 μglevonorgestrel/30 μg EE and 7 tablets each containing 30 μg of EE willbe white unembossed tablets. One combination tablet will be taken eachday for 84 days followed by 7 days of EE tablets in 91-day cyclesrepeated consecutively for approximately one year (4 cycles). EachDP3-84/30 dose kit will be packaged in a 3-part fold-out white blistercard pack where each of the first two blister packs has 28 activetablets each and the third blister pack has 28 active tablets and 7ethinyl estradiol tablets (35 tablets total) for each 91-day cycle.

Each blister card pack will be sealed into a foil pouch, which will belabeled with a patient-specific label. Each foil pouch will contain anoxygen absorber. At each clinic visit one foil pouch, a patientinformation sheet, a PPI and a child resistant pouch will be dispensed.

DP3-84/10

All tablets in the DP3-84/10 regimen; 84 tablets each containing 150-μglevonorgestrel/30-μg EE and 7 tablets each containing 10 μg of EE willbe white unembossed tablets. One combination tablet will be taken eachday for 84 days followed by 7 days of EE tablets in 91-day cyclesrepeated consecutively for approximately one year (4 cycles). EachDP3-84/10 dose kit will be packaged in a 3-part fold-out white blistercard pack where each of the first two blister packs has 28 activetablets each and the third blister pack has 28 active tablets and 7ethinyl estradiol tablets (35 tablets total) for each 91-day cycle.

Each blister card pack will be sealed into a foil pouch, which will belabeled with a patient-specific label. Each foil pouch will contain anoxygen absorber. At each clinic visit one foil pouch, a patientinformation sheet, a PPI and a child resistant pouch will be dispensed.

DP3-25/30

All tablets in the DP3-25/30 regimen; 25 tablets each containing 150-μglevonorgestrel/30-μg EE and 3 tablets each containing 30 μg of EE willbe white unembossed tablets. One combination tablet will be taken eachday for 25 days followed by 3 days of EE tablets in 28-day cyclesrepeated consecutively for approximately one year (13 cycles). EachDP3-25/30 blister card will have 25 active tablets followed by 3 ethinylestradiol tablets (28 tablets total) for each 28-day cycle.

Each blister card will be sealed into a foil pouch, which will belabeled with a patient-specific label. Each foil pouch will contain anoxygen absorber. At clinic visits one through three, 3 foil pouches, apatient information sheet, a PPI and a child resistant pouch will bedispensed. At clinic visit four, 4 foil pouches, a patient informationsheet, a PPI and a child resistant pouch will be dispensed.

All patients, regardless of randomization, will be instructed toinitiate OC therapy on the first Sunday following the beginning of theirmenstrual period (“Sunday starters”). Patients will be instructed totake their study medication at the same time each day. Day 1 of thestudy will be defined as the first day of study medication.

Administration

Designated personnel will dispense all study drugs. All studymedications must be kept in a secured area at temperature ranging fromapproximately 15-25° C. (59-77° F.). All patients will be instructed totake one tablet per day at approximately the same time each day. Allpatients will be “Sunday starters”; that is all patients will beginstudy drug therapy on the first Sunday following the start of theirprevious menstrual cycle or completion of prior oral contraceptiveregimens. All patients enrolled in the study will maintain Sunday startsfor each successive cycle.

The end-of-study evaluation will take place 1 week following completionof withdrawal menses following the last cycle of study OC therapy. Atthe clinic visit during which patients receive the final supply of studymedication, they will be counseled to use an alternative method of birthcontrol during the interval between when they have finished studymedication until they have completed the final study visit.

Patients randomized to DP3-84/30 or DP3-84/10 will receive a 13-weeksupply (single cycle) of study drug at each clinic visit during Weeks13, 26 and 39. Patients randomized to DP3-25/30 will receive a 12-weeksupply (three-cycles) of study drug at the initiation of the study andat clinic visits during Weeks 12 and 24. During the clinic visit at Week36 patients randomized to DP3-25/30 will receive 16-week supply (fourcycles) of study medication.

TABLE 5 Examinations/Tests Study Schedule Completion Parameter ScreeningVisit 1 Visits 2-4^(a) of Therapy Informed consent X Medical and Xcontraceptive history Physical exam including X X pelvic exam Weight,vital signs X X X X Pap smear X X Randomization X Clinical laboratorytests^(b) X X Urine pregnancy test^(c) X X X X Study drugdistribution^(d) X X Electronic diary X distribution Study drugcompliance X X measurement Adverse event recording X X ^(a)Patientsrandomized to DP3-84/30 or DP3-84/10 will be seen at Weeks 13, 26 and39. Patients randomized to DP3-25/30 will be seen at Weeks 12, 24, and40. ^(b)Clinical laboratory tests include CBC, serum chemistry, lipidprofile, urinalysis ^(c)Repeated on Visit 1 if the screening wascompleted more than 2 weeks prior to enrollment ^(d)For patientsrandomized to DP3 25/30, three (3) cycle supply will be dispensed atWeeks 12 and 24; a four (4) cycle supply will be dispensed at Week 40.

Study Procedures by Visit

Screening and Enrollment

Patients will sign informed consent. Prior to enrollment, within fourweeks prior to initiation of study therapy, all patients will undergo ascreening evaluation that will include prior medical and contraceptivehistory, smoking history, physical examination including pelvic exam andPap smear, vital signs and weight, and clinical laboratory testsincluding complete blood count (CBC), serum chemistry, lipid profile,urinalysis, and urine pregnancy test.

All clinical laboratory evaluations (blood and urine) will be tested bya central laboratory. All investigators will be provided with alaboratory manual that outlines sampling and shipping procedures.

If the screening evaluation is completed more than two weeks prior tothe initiation of study therapy, the urine pregnancy test must berepeated at Visit 1. Patients with a report of an abnormality on Papsmear will be disqualified for enrollment unless investigator decidesthe results are not clinically significant and will not interfere withconduct of the study. Investigator's decision must be documented.Patients who have had a normal Pap smear within the three months priorto enrollment in the study will not be required to have the testrepeated. A copy of the results must be available in the patient'smedical record. Any patient with a report of insufficient cells musthave the test repeated and documented as normal prior to enrollment.Patients will then be enrolled in the study.

Visit 1

Visit 1 will take place during the final week of the menstrual cycleprior to beginning study therapy (i.e., during menses for those patientsnot taking oral contraceptives or during Week 4 for those patientstaking oral contraceptives). During Visit 1 patients will be randomizedto one of the following treatment groups:

-   -   DP3-84/30; levonorgestrel 150 μg/EE 30 μg for 84 days+EE 30 μg        for 7 days        -   OR    -   DP3-84/10; levonorgestrel 150 μg/EE 30 μg for 84 days+EE 10 μg        for 7 days        -   OR    -   DP3-25/3; levonorgestrel 150 μg/EE 30 μg for 25 days+EE 30 μg        for 3 days

The treatment regimen assignment will be ascertained by randomizationvia Interactive Voice Response System (IVRS). The treatment groupassignment will not be revealed to the patient prior to signing of theinformed consent.

A urine pregnancy test will be re-administered to those women who werescreened more than two weeks prior to Visit 1. Study medication will bedispensed with patient instructions. An electronic diary will be givento each patient. Each patient will be trained regarding the use and careof the electronic diary. Patients will be instructed to take each doseof study medication and to complete all diary entries at approximatelythe same time each day.

Visits 2-4

All visits should take place within seven days prior to completion ofstudy medication for that cycle. Any visit that takes place prior to thefinal week of the cycle will be recorded as a protocol deviation. Anyvisit that takes place following the final week of the cycle resultingin a lapse in study medication intake will be recorded as a protocolviolation and will result in the patient being withdrawn from the study.Any visit that takes place following the final week of the cycle butdoes not result in a lapse in study medication (e.g., the patientreceived an emergency supply of study medication) will be recorded as aprotocol deviation.

Patients randomized to either DP3-84/30 or DP3-84/10 will be seen atWeeks 13, 26 and 39. Patients randomized to DP3-25/30 will be seen atWeeks 12, 24 and 36. During these visits, patients will be queriedregarding adverse events, concomitant medications, change in smokinghistory, and compliance. Vital signs and weight will be recorded. Aurine pregnancy test will be conducted. Used study medication will bereturned and counted by the study pharmacist or designated personnel.

Completion of Therapy

The end-of-study evaluation will take place 1 week following completionof last cycle of the study drug. Patients will be counseled to use birthcontrol during the interval between when they have finished studymedication until they have completed the final study visit. Patientswill undergo physical exam, including pelvic exam and pap smear. Vitalsigns and weight will be recorded. Blood and urine samples for clinicallaboratory tests including CBC, serum chemistry, lipid profile,urinalysis and urine pregnancy test will be obtained. Used studymedication cards will be returned and counted by the study pharmacist ordesignated personnel. Patients will be queried regarding adverse events,concomitant medications, change in smoking history and compliance. Theelectronic diary will be returned.

Post-Study Visit

After study completion/withdrawal, patients will be followed via a phonecall for occurrence of pregnancy and until the menstrual cycle returnsto normal. The patient based on the cycle pattern prior to the studyentry will determine return to normal menstrual cycle. The minimumperiod of follow up will be 3 months. Patients who decide to use acontraceptive method that regulates/alters menstrual cycle after studycompletion/withdrawal will be followed for 3 months via a phone call.

Only those patients who have an on-going serious adverse event that hasnot resolved or those who become pregnant during the course of the studywill be followed via clinic visits after completion of the study.Patients with on-going serious adverse events will be followed until theevent has been satisfactory managed or resolved. Patients who arepregnant will be followed for eight weeks following delivery ortermination of the pregnancy. Infants' health assessment will befollowed for eight weeks following delivery. This follow-up may be inthe form of a written report from a family physician, obstetrician orpediatrician. All serious adverse events that occur in the three monthsfollowing discontinuation of therapy will be reported. SAEs that occurat any time after study completion/discontinuation will be reported ifinvestigator determines it is drug-related.

Early Termination

Any patient who withdraws or is withdrawn from the study must return theinvestigational medication and electronic diary and will be required tocomplete all procedures for the final visit. All patients will befollowed via a phone call for 3 months for the occurrence of pregnancyand until the menstrual cycle return to normal. All patients will befollowed via a phone call for three months for the occurrence of seriousadverse events.

Examinations and Procedures

Physical Exam, Medical and Gynecologic History

A complete physical and gynecologic exam, including PAP smear, will beperformed at screening and at the completion of therapy or upon earlywithdrawal from the study. Any patient with an abnormal Pap smear willbe disqualified for enrollment unless investigator decides the resultsare not clinically significant and will not interfere with conduct ofthe study. The Investigator's decision must be documented. Patients whohave had a Pap smear reported as within normal limits within the threemonths prior to enrollment in the study will not be required to have thetest repeated. A copy of the results must be available in the patient'smedical record. Any patient with a report of insufficient cells musthave the test repeated and documented by the investigator as withinnormal limits prior to enrollment.

Laboratory Safety Tests

Clinical laboratory tests will be performed at screening and at thecompletion of therapy or upon early withdrawal. All clinical laboratorytests will be done at one central laboratory. Laboratory tests willinclude CBC, serum chemistry, lipid profile, urinalysis, and urinepregnancy test. In addition, urine pregnancy tests will be conducted atevery clinic visit and at the completion of therapy or upon earlywithdrawal from the study. All urine pregnancy tests will be performedusing the Sure Steps Pregnancy Test kit (Applied Biotech, Inc.).

Pregnancy

All patients will be followed for the occurrence of pregnancy for threemonths following completion of the study. This follow-up may be in theform of a telephone call. All pregnancies that occur during the courseof the study or in the three months following completion of the studywill be dated using ultrasound to establish the gestational age of thefetus. Patients who become pregnant during the course of the study dueto method failure will be followed for eight weeks following delivery ortermination of the pregnancy. Infants' health assessment will befollowed for eight weeks following delivery. This follow-up may in theform of a documented telephone conversation with associated pediatricianor written report from the associated pediatrician.

Electronic Diaries

Patients will be asked to complete electronic diaries. The diary will beprogrammed to ask specific questions related to the study compliance,bleeding pattern and occurrence of symptoms that are commonly associatedwith the hormone fluctuation during the menstrual cycle. The questionswill address dosage, compliance, bleeding pattern and hormone-relatedsymptoms either on the scale from 0-3 or using 10 cm Visual AnalogueScale (VAS).

Hand-held data acquisition devices will be used to collect patientresponses. The electronic diary will provide patients with amenu-driven, graphical interface to enter diary information (as well asobjective data) using a hand-held stylus. Data entry will be electronicand key fields must be completed properly before allowing patient tofinish the report. Each report will be downloaded by dial-up networkconnection.

The electronic diary will incorporate an alarm to remind the patientwhen to complete their reports. Alarm times will be set by the site andcan be specific to the patient preference. The patient will beinstructed to complete a diary on a daily basis. Retrospective dataentry will not be allowed; reports cannot be completed for previousdays. Once each question is completed the patient will confirm theresponse and will not be permitted to return to that question formodification.

Information on the hormone-related symptoms to be collected is from theCalendar of Premenstrual Experiences (COPE) and Diagnostic andStatistical Manual of Mental Disorders Forth Edition (DSM-IV).

The validity and reliability of the COPE instrument was assessed byMortola, et al., Obstet. Gynecol. 89:179-83 (1990), who administered itthroughout two consecutive ovulatory cycles to 36 rigidly screened womenwith PMS and to 18 controls. The validity of the visual analogue scalesapplied to the psychological symptoms associated with the PMDD has beenpreviously documented.

Treatment Modifications Based on Toxicity

No significant toxicity is expected from the study medication. However,if the patient develops any symptoms or any abnormal laboratoryparameter attributed to the drug, which are considered by the patientand/or physician to be of unacceptable severity, then the studymedication should be discontinued.

Concomitant Medications

Patients will be queried regarding concomitant medication use at monthlyphone calls and quarterly clinic visits. All concomitant medication use(both prescription and over-the-counter (OTC), including herbalmedications and nutritional supplements) must be reported during thestudy, and recorded on the patient's Case Report Form (CRF).

Patients who require the initiation of chronic therapy with drugs thatare known to interact with OCs will be withdrawn from the study.Patients who require intermittent therapy with drugs known to interactwith OCs (e.g. antibiotic therapy) will remain in the study and willreceive counseling regarding the need for additional contraceptiveprotection during the entire cycle. Patients will be provided with thelist of medications that are know to interact with OC and will beinstructed to notify study coordinator as soon as medication isprescribed to receive proper counseling. Notification and counseling canbe conducted via the phone and must be documented in the patient's CRF.Those cycles in which drugs known to interact with OC therapy are takenwill not be used in the calculation of the pregnancy rate.

The use of emergency contraceptive pills (“morning after pills”) isprohibited in the study. Data from any patient who utilizescontraceptive pills others than those provided for the study will not beincluded in the calculation of the pregnancy rate for that cycle.

Adverse Event Reporting

An Adverse Event (AE) is any reaction, side effect, or other undesirableevent that occurs in conjunction with the use of a drug, biologicalproduct or diagnostic agent in humans, whether or not the event isconsidered drug related.

A serious adverse event (SAE) is one that meets any one of the followingcriteria:

-   -   Fatal or life threatening    -   Requires or prolongs inpatient hospitalization    -   Results in persistent or significant disability/incapacity    -   Congenital anomaly

The term “life threatening” in the definition of “serious” refers to anevent in which the patient was at risk of death at the time of theevent; it does not refer to an event that hypothetically might havecaused death if it were more severe. Medical and scientific judgmentshould be exercised in deciding whether an important medical event isserious. Although the event may not be immediately life threatening,fatal, or result in hospitalization, it should be considered seriouswhen it jeopardizes the patient, or requires an intervention to preventa serious outcome as defined above.

The AE reporting period for this study begins at the Enrollment Visitand ends at the final clinic visit. The SAE reporting period willcontinue for 3 month after the final clinic visit. All SAEs will befollowed through resolution or until investigator assesses the SAE aschronic or stable.

A preexisting condition (i.e., a disorder present before the AEreporting period started and noted on the pretreatment medicalhistory/physical form) should not be reported as an AE unless thecondition worsens or episodes increase in frequency during the AEreporting period.

During the study AEs will be recorded through monthly phone calls andquarterly clinic visits. A call-in number will be provided to thepatients who wish to report an adverse event between the scheduled phonecalls and clinic visits.

Example 2 Multicenter Randomized Phase III Clinical Trial to EvaluateTwo Continuous Oral Contraceptive Regimens in Combination withFluoxetine Hydrochloride in Women Diagnosed with Premenstrual Syndrome(PMS) and Premenstrual Dysphoric Disorder (PMDD)

Overview of the Study Design

In a three-arm, parallel, randomized, multicenter, placebo-controlled,double-blinded study, the efficacy and safety of continuous oralcontraceptive therapy as a ninety-one day regimen (84 days activecombination therapy followed by low dose estrogen for 7 consecutive days(DP3-91)), or as a twenty-eight day regimen (21 day active combinationtherapy followed by low dose estrogen for 7 consecutive days (DP3-28)),in combination with fluoxetine hydrochloride administered forapproximately 6 consecutive months to women diagnosed with PMS and/orPMDD who desire contraception, will be evaluated.

A cohort of approximate 40-100 patients enrolled in each of the studyarms will undergo endometrial biopsy (to test incidence of hyperplasiaand carcinoma) prior to the initiation of study drug therapy and at theconclusion of the study or withdrawal.

Efficacy of the 28-day and 91-day regimens on premenstrualsymptomatology will be measured by psychometric scales that includeself-administered Visual Analogue Scales (VAS) and a prospective dailysymptoms chart to evaluate psychological and somatic symptoms. The VASmeasures tension, irritability, dysphoria, sleeping and eating patterns,headache, bloating, pain and breast tenderness and weight gain symptoms.Total score of the psychological and somatic symptoms will be computed.The patient and blind observer will also complete the PMTS at eachvisit.

Study Population

Females ages 18 through 49 who are fluent in English and capable ofgiving informed consent, without contraindication to the use of oralcontraceptives and selective serotonin reuptake inhibitors (SSRIs), andmeet the criteria for PMS including PMDD as defined in the diagnosticand statistical manual of mental disorders (DSM-IV). All patients willbe counseled at the beginning of the study and at each study visit touse an alternative form of contraception. All patients will be followedfor the occurrence of pregnancy during the course of the study. Patientswho become pregnant during the course of the study will be followed foreight weeks following delivery or termination of the pregnancy. Infantswill be followed for eight weeks following delivery.

Dosage

Patients will be randomized to one of the following:

(1) Ninety-one day oral contraceptive therapy with ethinyl estradiol(DP3-91) and fluoxetine hydrochloride administered for two cycles whereeach cycle consists of: 150 μg levonorgestrel and 30 μg ethinylestradiol (days 1-84 of the first cycle and days 92-175 of the secondcycle, 30 μg ethinyl estradiol (days 85-91 of the first cycle and days176-182 of the second cycle), 20 mg fluoxetine hydrochloride (days1-182), and placebo to preserve blinding (days 183-196);(2) Twenty-eight day oral contraceptive therapy with ethinyl estradiol(DP3-28) administered for 7 cycles where each cycle consists of: 150 μglevonorgestrel and 30 μg ethinyl estradiol (days 1-21 for seven cycles),30 μg ethinyl estradiol (days 22-28 for seven cycles), and 20 mgfluoxetine hydrochloride (days 1-196); or

(3) Fluoxetine hydrochloride administered daily for 196 days: 20 mgfluoxetine hydrochloride per day (days 1-196) or placebo to preserveblinding (days 1-196).

Study Management

The study will utilize electronic case report forms and remote systemmanagement. Each investigator will be provided a programmed laptopcomputer dedicated to the study. This system allows the investigator todownload and view patient diary data during clinic visits and alsoallows for rapid data queries by the study monitors. The system willalso allow real-time on-line tracking of study site accrual rates,serious adverse events, pregnancies and study progress.

Outcomes Measurement Scales

The primary outcome will be defined as reduction in symptoms of PMSincluding PMDD as measured by the mean scores on Visual Analogue Scales(VAS) and the Premenstrual Tension Syndrome Scale (PMTS). The VAS willmeasure tension, irritability, dysphoria, sleeping and eating patterns,headache, bloating, pain and breast tenderness symptoms. Patients willbe prompted to rate how they feel each day using 100 mm scales in whichthe descriptors range from “no symptoms” (0 mm) to “severe or extremesymptoms” (100 mm). The PMTS consists of a 36 item scale that will becompleted by the patient and a 10-item scale completed by the blindedobserver. Both scales rate premenstrual symptoms for a particular day;the total score can range from 0 (no symptoms) to 36 (all symptomspresent and severe).

The secondary outcome will be defined as reduction in symptoms of PMSincluding PMDD as measured by the sub-score of somatic symptoms on VAS.The VAS will measure headache, bloating, pain and breast tenderness andweigh gain symptoms. Patients will be prompted to rate how they feeleach day using 100 mm scales in which the descriptors range from “nosymptoms” (0 mm) to “severe symptoms” (100 mm). In addition toinformation recorded in paper diaries, a standardized questionnaire willbe used to determine whether the patient had any side effects.

Statistical Analysis

For the primary analysis, the mean of the VAS scales will be derived toobtain a single VAS score, which evaluates composite psychological andsymptomatic outcomes. Mean percent reduction from baseline at the lutealphase will be compared using an analysis of covariance (ANCOVA) approachthat evaluates the effects of the treatment group, center andtreatment-by-center interaction, after adjusting for the effect of thebaseline VAS score. All statistical tests will be two-sided at the 0.05level of significance. Pairwise comparisons will be made for each activetreatment to placebo. Secondary analyses will include a set ofstatistical tests for the PMTS and 10-item blinded observer-basedmeasures.

Application of the compounds, compositions and methods of the presentinvention for the medical or pharmaceutical uses described can beaccomplished by any clinical, medical, and pharmaceutical methods andtechniques as are presently or prospectively known to those skilled inthe art. It will therefore be appreciated that the various embodimentswhich have been described above are intended to illustrate the inventionand various changes and modifications can be made in the inventivemethod without departing from the spirit and scope thereof.

1-83. (canceled)
 84. A preparation comprising (a) 81 to 89 dosage formscomprising a combination of estrogen and progestin; and (b) 2 to 8dosage forms consisting essentially of estrogen, wherein: the estrogenin each of the 81 to 89 dosage forms comprising the combination ofestrogen and progestin in (a) is present in an amount equivalent toabout 10 μg to about 50 μg of ethinyl estradiol; the estrogen in each ofthe 2 to 8 dosage forms consisting essentially of estrogen in (b) ispresent in an amount equivalent to about 5 μg to about 10 μg ethinylestradiol; and the progestin in each of the dosage forms comprising thecombination of estrogen and progestin in (a) is present in an amount ofabout 50 μg to about 150 μg of levonorgestrel.
 85. The preparation ofclaim 84, wherein the estrogen in the each of the 81 to 89 dosage formscomprising the combination of estrogen and progestin in (a) is presentin an amount equivalent to about 10 μg to about 30 μg of ethinylestradiol.
 86. The preparation of claim 84, wherein the estrogen in eachof the 81 to 89 dosage forms comprising the combination of estrogen andprogestin in (a) is present in an amount equivalent to about 30 μg ofethinyl estradiol.
 87. The preparation of claim 84, wherein the estrogenin each of the 2 to 8 dosage forms consisting essentially of estrogen in(b) is present in an amount equivalent to about 10 μg ethinyl estradiol.88. The preparation of claim 84, wherein the progestin in each of thedosage forms comprising the combination of estrogen and progestin in (a)is present in an amount of about 150 μg of levonorgestrel.
 89. Thepreparation of claim 84, wherein the preparation comprises 84 dosageforms in (a).
 90. The preparation of claim 84, wherein the preparationcomprises 5-8 dosage forms in (b).
 91. The preparation of claim 84,wherein the preparation comprises 7 dosage forms in (b).
 92. Thepreparation of claim 84, wherein the preparation comprises 84 dosageforms in (a) and 7 dosage forms in (b).
 93. The preparation of claim 84,wherein the estrogen is ethinyl estradiol.
 94. The preparation of claim84, wherein the preparation further comprises an antidepressant, andwherein the antidepressant is administered (i) in combination with the 2to 8 dosage forms consisting essentially of estrogen, (ii)intermittently, (iii) one time, or (iv) once weekly.
 95. The preparationof claim 94, wherein the antidepressant administered in combination withthe dosage forms consisting essentially of estrogen is administered with5 to 8 dosage forms consisting essentially of estrogen.
 96. Thepreparation of claim 84, wherein the dosage forms are tablets for oraladministration.
 97. The preparation of claim 84, wherein the dosageforms are transdemal dosage forms for transdermal administration.
 98. Apreparation comprising (a) 84 dosage forms comprising a combination ofestrogen and progestin; and (b) 7 dosage forms consisting essentially ofestrogen, wherein: the estrogen in each of the 84 dosage formscomprising the combination of estrogen and progestin in (a) is presentin an amount of about 10 μg to about 30 μg of ethinyl estradiol; theestrogen in each of the 7 dosage forms consisting essentially ofestrogen in (b) is present in an amount of about 10 μg ethinylestradiol; the progestin in each of the dosage forms comprising thecombination of estrogen and progestin in (a) is present in an amount ofabout 50 μg to about 150 μg of levonorgestrel; and wherein the dosageforms in (a) and (b) are tablets for oral administration.
 99. Apreparation comprising (a) 84 dosage forms comprising a combination ofestrogen and progestin; and (b) 7 dosage forms consisting essentially ofestrogen, wherein: the estrogen in each of the 84 dosage formscomprising the combination of estrogen and progestin in (a) is presentin an amount of about 30 μg of ethinyl estradiol; the estrogen in eachof the 7 dosage forms consisting essentially of estrogen in (b) ispresent in an amount of about 10 μg ethinyl estradiol; the progestin ineach of the dosage forms comprising the combination of estrogen andprogestin in (a) is present in an amount of about 150 μg oflevonorgestrel; and wherein the dosage forms in (a) and (b) are tabletsfor oral administration.
 100. A kit comprising (a) 84 tablets for oraladministration comprising a combination of estrogen and progestin; and(b) 7 tablets for oral administration consisting essentially ofestrogen, wherein: the estrogen in each of the 84 tablets comprising thecombination of estrogen and progestin in (a) is present in an amount ofabout 10 μg to about 30 μg of ethinyl estradiol; the estrogen in each ofthe 7 tablets consisting essentially of estrogen in (b) is present in anamount of about 10 μg ethinyl estradiol; the progestin in each of thetablets comprising the combination of estrogen and progestin in (a) ispresent in an amount of about 50 μg to about 150 μg of levonorgestrel;and wherein the tablets in (a) and (b) are arranged in a fixed sequencethat corresponds to the stages of daily administration.
 101. A kitcomprising (a) 84 tablets for oral administration comprising acombination of estrogen and progestin; and (b) 7 tablets for oraladministration consisting essentially of estrogen, wherein: the estrogenin each of the 84 tablets comprising the combination of estrogen andprogestin in (a) is present in an amount of about 30 μg of ethinylestradiol; the estrogen in each of the 7 tablets consisting essentiallyof estrogen in (b) is present in an amount of about 10 μg ethinylestradiol; the progestin in each of the tablets comprising thecombination of estrogen and progestin in (a) is present in an amount ofabout 150 μg of levonorgestrel; and wherein the tablets in (a) and (b)are arranged in a fixed sequence that corresponds to the stages of dailyadministration.
 102. A preparation comprising (a) 81 to 89 dosage formscomprising a combination of estrogen and progestin; and (b) 2 to 8dosage forms consisting essentially of estrogen, wherein: the estrogenin each of the 81 to 89 dosage forms comprising the combination ofestrogen and progestin in (a) is present in an amount equivalent toabout 10 μg to about 30 μg of ethinyl estradiol; the estrogen in each ofthe 2 to 8 dosage forms consisting essentially of estrogen in (b) ispresent in an amount equivalent to about 30 μg ethinyl estradiol; andthe progestin in each of the dosage forms comprising the combination ofestrogen and progestin in (a) is present in an amount of about 50 μg toabout 150 μg of levonorgestrel.
 103. The preparation of claim 102,wherein the estrogen in each of the 81 to 89 dosage forms comprising thecombination of estrogen and progestin in (a) is present in an amountequivalent to about 30 μg of ethinyl estradiol.
 104. The preparation ofclaim 102, wherein the progestin in each of the dosage forms comprisingthe combination of estrogen and progestin in (a) is present in an amountof about 150 μg of levonorgestrel.
 105. The preparation of claim 102,wherein the preparation comprises 84 dosage forms in (a).
 106. Thepreparation of claim 102, wherein the preparation comprises 5-8 dosageforms in (b).
 107. The preparation of claim 102, wherein the preparationcomprises 7 dosage forms in (b).
 108. The preparation of claim 102,wherein the preparation comprises 84 dosage forms in (a) and 7 dosageforms in (b).
 109. The preparation of claim 102, wherein the estrogen isethinyl estradiol.
 110. The preparation of claim 102, wherein thepreparation further comprises an antidepressant, and wherein theantidepressant is administered (i) in combination with the 2 to 8 dosageforms consisting essentially of estrogen, (ii) intermittently, (iii) onetime, or (iv) once weekly.
 111. The preparation of claim 110, whereinthe antidepressant administered in combination with the dosage formsconsisting essentially of estrogen is administered with 5 to 8 dosageforms consisting essentially of estrogen.
 112. The preparation of claim102, wherein the dosage forms are tablets for oral administration. 113.The preparation of claim 102, wherein the dosage forms are transdemaldosage forms for transdermal administration.
 114. A preparationcomprising (a) 84 dosage forms comprising a combination of estrogen andprogestin; and (b) 7 dosage forms consisting essentially of estrogen,wherein: the estrogen in each of the 84 dosage forms comprising thecombination of estrogen and progestin in (a) is present in an amount ofabout 30 μg of ethinyl estradiol; the estrogen in each of the 7 dosageforms consisting essentially of estrogen in (b) is present in an amountof about 30 μg ethinyl estradiol; the progestin in each of the dosageforms comprising the combination of estrogen and progestin in (a) ispresent in an amount of about 150 μg of levonorgestrel; and wherein thedosage forms in (a) and (b) are tablets for oral administration.
 115. Akit comprising (a) 84 tablets for oral administration comprising acombination of estrogen and progestin; and (b) 7 tablets for oraladministration consisting essentially of estrogen, wherein: the estrogenin each of the 84 tablets comprising the combination of estrogen andprogestin in (a) is present in an amount of about 30 μg of ethinylestradiol; the estrogen in each of the 7 tablets consisting essentiallyof estrogen in (b) is present in an amount of about 30 μg ethinylestradiol; the progestin in each of the tablets comprising thecombination of estrogen and progestin in (a) is present in an amount ofabout 150 μg of levonorgestrel; and wherein the tablets in (a) and (b)are arranged in a fixed sequence that corresponds to the stages of dailyadministration.
 116. A preparation comprising (a) 21 dosage formscomprising a combination of estrogen and progestin; and (b) 7 dosageforms consisting essentially of estrogen, wherein: the estrogen in eachof the 21 dosage forms comprising the combination of estrogen andprogestin in (a) is present in an amount equivalent to about 10 μg toabout 50 μg of ethinyl estradiol; the estrogen in each of the 7 dosageforms consisting essentially of estrogen in (b) is present in an amountequivalent to about 5 μg to about 10 μg ethinyl estradiol; and theprogestin in each of the dosage forms comprising the combination ofestrogen and progestin in (a) is present in an amount of about 50 μg toabout 150 μg of desogestrel.
 117. The preparation of claim 116, whereinthe estrogen in the each of the 21 dosage forms comprising thecombination of estrogen and progestin in (a) is present in an amountequivalent to about 10 μg to about 30 μg of ethinyl estradiol.
 118. Thepreparation of claim 116, wherein the estrogen in each of the 7 dosageforms consisting essentially of estrogen in (b) is present in an amountequivalent to about 10 μg ethinyl estradiol.
 119. The preparation ofclaim 116, wherein the progestin in each of the dosage forms comprisingthe combination of estrogen and progestin in (a) is present in an amountof about 150 μg of desogestrel.
 120. The preparation of claim 116,wherein the estrogen is ethinyl estradiol.
 121. The preparation of claim116, wherein the preparation further comprises an antidepressant, andwherein the antidepressant is administered (i) in combination with the 2to 8 dosage forms consisting essentially of estrogen, (ii)intermittently, (iii) one time, or (iv) once weekly.
 122. Thepreparation of claim 121, wherein the antidepressant administered incombination with the dosage forms consisting essentially of estrogen isadministered with 5 to 8 dosage forms consisting essentially ofestrogen.
 123. The preparation of claim 116, wherein the dosage formsare tablets for oral administration.
 124. The preparation of claim 116,wherein the dosage forms are transdemal dosage forms for transdermaladministration.
 125. A preparation comprising (a) 21 dosage formscomprising a combination of estrogen and progestin; and (b) 7 dosageforms consisting essentially of estrogen, wherein: the estrogen in eachof the 21 dosage forms comprising the combination of estrogen andprogestin in (a) is present in an amount of about 10 μg to about 30 μgof ethinyl estradiol; the estrogen in each of the 7 dosage formsconsisting essentially of estrogen in (b) is present in an amount ofabout 10 μg ethinyl estradiol; and the progestin in each of the dosageforms comprising the combination of estrogen and progestin in (a) ispresent in an amount of about 150 μg of desogestrel; and wherein thedosage forms in (a) and (b) are tablets for oral administration.
 126. Akit comprising (a) 21 tablets for oral administration comprising acombination of estrogen and progestin; and (b) 7 tablets for oraladministration consisting essentially of estrogen, wherein: the estrogenin each of the 21 tablets comprising the combination of estrogen andprogestin in (a) is present in an amount of about 10 μg to about 30 μgof ethinyl estradiol; the estrogen in each of the 7 tablets consistingessentially of estrogen in (b) is present in an amount of about 10 μgethinyl estradiol; the progestin in each of the tablets comprising thecombination of estrogen and progestin in (a) is present in an amount ofabout 150 μg of desogestrel; and wherein the tablets in (a) and (b) arearranged in a fixed sequence that corresponds to the stages of dailyadministration.